Posterior urethral valves (PUV) are the major cause of severe obstructive uropathy in male children and account for 17% of pediatric end-stage renal disease. Despite the severity of the disease and its impact on mortality and morbidity, the molecular basis of this condition is largely unknown, resulting in suboptimal diagnostic and therapeutic strategies. The epidemiology of the disease, characterized by high selective pressure versus a phenotype with low fitness, suggests that dominant de novo mutations or recessive inheritance play a major role in disease determination. Here we propose to apply exome sequencing to 100 trios composed of two unaffected parents and a child affected by congenital posterior urethral valves to rapidly identify de novo pathogenic mutations or uncover recessive alleles. To prioritize candidate genes we will perform cross-annotation with CNV data from 2,000 patients with urinary tract malformations including PUV, and with gene expression signatures from Sall1 knockout mice available in the lab through Cathy Mendelsohn (Project 2). We will finally replicate the high-priority genes by resequencing 1,000 independent patients using the Fluidigm targeted enrichment system coupled to next-generation sequencing to identify independent mutations and establish causation. To address these objectives we will apply novel genomic tools to accurately formulate genetic diagnosis, individualize medical care, and generate new hypotheses by providing the community with a catalogue of new variants and genes to be tested by investigators in the field.